A new structural model of Alzheimer's A?42 fibrils based on electron paramagnetic resonance data and Rosetta modeling.

ABSTRACT: Brain deposition of A? in the form of amyloid plaques is a pathological hallmark of Alzheimer's disease. There are two major species of A? in the brain: A?42 and A?40. Although A?40 is several-fold more abundant than A?42 in soluble form, A?42 is the major component of amyloid plaques. Structural knowledge of A?42 fibrils is important both for understanding the process of A? aggregation and for designing fibril-targeting drugs. Here we report site-specific structural information of A?42 fibrils at 22 residue positions based on electron paramagnetic resonance data. In combination with structure prediction program Rosetta, we modeled A?42 fibril structure at atomic resolution. Our A?42 fibril model consists of four parallel in-register ?-sheets: ?N (residues ?7-13), ?1 (residues ?17-20), ?2 (residues ?32-36), and ?C (residues 39-41). The region of ?1-loop-?2 in A?42 fibrils adopts similar structure as that in A?40 fibrils. This is consistent with our cross seeding data that A?42 fibril seeds shortened the lag phase of A?40 fibrillization. On the other hand, A?42 fibrils contain a C-terminal ?-arc-? motif with a special turn, termed "arc", at residues 37-38, which is absent in A?40 fibrils. Our results can explain both the higher aggregation propensity of A?42 and the importance of A?42 to A?40 ratio in the pathogenesis of Alzheimer's disease.

SUBMITTER: Gu L 

PROVIDER: S-EPMC4764428 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature